Congenital ataxia presents in early childhood with non-progressive hypotonia, cognitive, gross and fine motor delays. These disorders are distinct from the progressive ataxias because of the presence of congenital cerebellar malformations and recessive modes of inheritance. Joubert Syndrome and Related Disorders (JSRD) constitutes a subset of these conditions, consisting of a cerebella midline (vermis) malformation, and a nearly pathognomonic Molar Tooth sign on brain Imaging (MTI). There is significant phenotypic heterogeneity in JSRD: some patients display the classical form (limited to brain), and others display additionally congenital retinal blindness, progressive kidney failure, cerebral cortical abnormalities or a striking brain wiring phenotype in which each cerebral cortical hemisphere projects output to the ipsilateral side of the body, but receives sensory information from the contralateral side. The cellular and developmental bases of these conditions are not understood. Mutations in two genes, NPHP1 and AHI1, are associated with JSRD. In an exciting new development, we identified the third JSRD gene, CEP290 (submitted). Compelling evidence suggests these proteins function at the cilia/centrosome. Here we propose to apply molecular techniques to study roles of these three genes by performing mutational analyses, genotype-phenotype correlations, test the encoded proteins for a possible role in cilia-based intraflagellar transport, and test animal models for defects in neuronal proliferation and axon guidance. Together this data will provide a framework to understand the role of these genes in the spectrum of conditions seen in JSRD. 1. We will perform comprehensive mutation analysis and genotype-phenotype correlations in a cohort of 180 JSRD probands to test the hypothesis that NPHP1 or CEP290 mutations are associated with JSRD plus kidney failure, whereas AHI1 mutations are associated with JSRD plus cortical abnormalities. 2. We will test the possibility that these genes function at the cilia/centrosome to mediate transduction of Wnt or Sonic Hedgehog signals, using loss- and gain-of-function analyses. 3. We will analyze the brain phenotype of mice with targeted deletions of each gene to test whether these pathways regulate cerebella granule neuron proliferation and axon guidance.